Category: Autoimmune neurologic diseases
B cells are strongly implicated in new multiple sclerosis (MS) relapses, through antibody-independent functions including antigen presentation and pro-inflammatory cytokine-mediated activation of T cells and myeloid cells. B cells also persist in meninges of patients where they are now thought contribute to non-relapsing (progressive disease) mechanisms. Therapies able to target B cells within the CNS may effectively limit disease progression. Bruton’s Tyrosine Kinase (BTK) plays a crucial role in early B cell development. Specific BTK inhibitors have now been used for treatment of B cell malignancies and some can access the CNS. Here, we studied the impact of BTK inhibition (BTKi) on human B cell functions. Using purified peripheral CD19+B cells from healthy volunteers or MS patients as well as human tonsillar B cells, we show that the presence of BTKi strongly decreased B cell activation (limiting up-regulation of CD69 and CD40) without apparently affecting B cell survival. BTKi significantly limited the induction of co-stimulatory molecule (CD80, CD86) expression on activated B cells, which in turn resulted in a decreased capacity of the B cells to support both polyclonal as well as antigen-specific T cell activation. Finally, BTKi treatment also significantly reduced pro-inflammatory B-cell cytokine (GM-CSF, TNF-alpha and IL-6) secretion with only marginal influence on B cell IL-10 production, resulting in a decreased capacity of the B cells to promote myeloid cell pro-inflammatory responses. BTKi may thus effectively limit antibody-independent pro-inflammatory B cell responses that are now implicated in both peripherally-mediated relapsing disease, and in CNS-compartmentalized progressive disease.
Rui Li– Post-doctoral, Perelman School of Medicine, University of Pennsylvania
Hao Tang– MS Research Unit, Biogen
Bin Ma– MS Research Unit, Biogen
Hopkins Brian– MS Research Unit, Biogen
Michaël Mingueneau– Biogen
Amit Bar-Or– Melissa and Paul Anderson President’s Distinguished Professor, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania